Abstract
Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 and FOXM1, (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation and (vi) possible connection between methionine metabolism and pluripotency, protein synthesis through cholesterol metabolism: SREBF2-FOXM1 and ACA43 axis, respectively. (vii) Disruption of autophagy by insufficient formation of macroautophagosomes. In conclusion, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis, ribosomal RNA and autophagy.
REGULATION OF CHOLESTEROL BIOSYNTHESIS IN CULTURED CELLS OF NEURAL ORIGIN
